This is a competitive renewal of NIH grant DK62071 entitled Hepatic Insulin Resistance Following Hemorrhage which focuses on studying the acute development of insulin resistance following injury. Over the past 5 years we have studied the mechanisms and causative factors that result in an acute insulin resistant state that occurs in animals, as in humans, after injury, infection or critical illness. Insulin resistance and hyperglycemia are characteristic metabolic responses to infections and injury such as surgery, burns, trauma and hemorrhage. Intensive insulin treatment of patients in the surgical ICU reduces both morbidity and mortality associated with critical illness, at least in some situations. However, intensive insulin therapy increases the likelihood of deleterious hypoglycemic incidents. Insulin is a primary modulator of hepatic glucose output, but little is known concerning the role of hepatic insulin resistance in the development of hyperglycemia following injury. Thus, it is important to understand what causes hepatic insulin resistance. Insulin resistance can be explained by changes in the number of insulin receptors or their activity, or a post- receptor defect. Recently published and preliminary data indicate that there are insulin receptor and post-receptor defects in insulin signaling that develop in the liver following surgical trauma alone, and to an even greater degree following the combination of trauma and hemorrhage. Our recent preliminary data also indicates that the initial development of hepatic insulin resistance is not dependent upon proinflammatory cytokines. Additional preliminary data indicate that the mechanisms of the development of insulin resistance are different in the three main insulin target tissues, liver, skeletal muscle and adipose tissue. This makes it necessary to study each tissue separately, to determine how this insulin resistance occurs. However, this has a possible advantage of eventually being able to specifically target individual tissues, with treatments less likely than intensive insulin therapy to cause hypoglycemic incidents. In addition, understanding the development of insulin resistance may be important in determining the proper application of intensive insulin therapy, and under what conditions this therapy might do the most good. Thus, studies are proposed in this application to determine the mechanism(s) of the development of acute insulin resistance in liver. Potential clinical treatments are explored that may work to reverse the mortality and morbidity related to hyperglycemia and insulin resistance in the critical care setting. These studies are important in understanding the role of insulin resistance in the morbidity and mortality following injury, infection and critical illness.